DEMONSTRATED THAT TH ACTIVATES XENOPUS MBD3 GENE VIA AN INTRONIC TRE DURING INTESTINAL STEM CELL DEVELOPMENT. To identify direct TH response genes during the formation of adult intestinal stem cells, we previously carried out a ChIP (chromatin immunoprecipitation)-on-chip analysis with a polyclonal anti-TR antibody on the tadpole intestine and identified many putative TR target genes. Among them is the methyl-CpG binding domain protein 3 (MBD3) gene, which has been implicated to play a role in epigenetic regulation of cellular processes as a subunit of the Mi-2/NuRD (Nucleosome Remodeling Deacetylase) complex. We have now shown that MBD3 is upregulated in the intestine by TH and its expression peaks at stage 62, the climax of metamorphosis. We have further discovered a putative TRE within the first intron of the MBD3 gene that binds to TR/RXR in vitro and in vivo, and mediates TH regulation of the MBD3 promoter in vivo. DISCOVERED THAT TR MUTATIONS LEAD TO EPITHELIAL DEFECTS IN THE ADULT INTESTINE IN A MOUSE MODEL OF RESISTANCE TO THYROID HORMONE. Intestinal maturation in mammals takes place around birth when TH levels are high, mimicking frog metamorphosis and implicating a role of TH in mammalian intestinal development and function. Interestingly, a number of human patients carrying heterozygous mutations in the TR gene (RTH, or resistance to TH due to TR mutation) have been discovered in recent years and found to have constipation, implicating intestinal defects caused by TR gene mutations. To determine how TR1 mutations affect the intestine, we have analyzed a mutant mouse expressing a strong dominantly negative TR1 mutant, (denoted TR1PV; Thra1PV mice). This mutant mouse faithfully reproduces RTH phenotypes as observed in human patients. In adult Thra1PV/+ mice, we observed constipation just like in patients with TR mutations. Importantly, we discovered significant intestinal defects, including shorter villi, increased differentiated cells in the crypt, accompanied by reduced stem cell proliferation in the intestine. Our findings suggest an evolutional conservation of TH function in the intestine. Further analysis of this mouse model should help reveal the molecular and physiological defects in the intestine caused by TR mutations and to determine the underlying mechanisms. DISCOVERED THAT LAT1 REGULATES OSTEOCLASTOGENESIS AND BONEHOMEOSTASIS THROUGH THE MTORC1 PATHWAY. To regulate cellular processes, TH has to be actively transported into cells and this process is mediated by several different types of transporters. One of our previously identified TH-response genes in the intestine, LAT1, encodes the light chain of a heterodimeric system L type of TH transporter, which also transports several amino acids. Interestingly, LAT1 is highly upregulated at the climax of metamorphosis in the tadpole intestine, coinciding with the formation and rapid proliferation of the adult intestinal stem cells. We also found out that LAT1 was also highly expressed in the mouse intestine during the neonatal period when the mouse intestine matured into the adult form, a process that appears also involves TH-dependent formation and/proliferation of the adult intestinal stem cells. Through a collaborative study, we generated a mouse line with the LAT1 gene floxed, which allows conditional knockout of the LAT1 upon expression of the Cre recombinase. While we are still in the process to investigate whether LAT1 affects adult intestinal stem cell development in mouse, we have recently shown through another collaboration that LAT1 is an important amino acid transporter for the regulation of bone homeostasis through its function in osteoclasts. LAT1 expression was significantly decreased in osteoclasts in a mouse model of ovariectomy-induced osteoporosis. The osteoclast-specific deletion of LAT1 in mice led to osteoclast activation and bone loss in vivo, and LAT1 deficiency increased osteoclastogenesis in vitro. Loss of LAT1 impaired activation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in osteoclasts, whereas genetic activation of mTORC1 corrected the activation of osteoclastogenesis and bone loss due to LAT1 deficiency. These findings suggest that the LAT1-mTORC1 axis might play a pivotal role in bone resorption and bone homeostasis, thereby providing a novel molecular connection between amino acid intake and skeletal integrity.